Regulatory mechanism for key protein is more active for humans

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A gene known to be important for brain development is more active in humans than in apes, a discovery that might have played a key role in human evolution.

The gene is used by cells to make an opiatelike protein found in apes and humans called "prodynorphin," or PDYN.

In humans, PDYN is believed to be important for perception, memory and susceptibility to drug dependence. People who don’t make enough of the protein are vulnerable to drug addiction, schizophrenia, bipolar disorder and a form of epilepsy, studies have found.

"So we reasoned that humans might uniquely need to make more of this substance, perhaps because our brains are bigger, or because they function differently," said Gregory Wray, a biologist at the Duke University in North Carolina who was involved in the study.

The researchers found that humans possess a distinctive variant in a regulatory segment of the gene that causes PDYN to be produced in higher concentration than in apes.

Altering the regulatory segments of a gene is often a better way to generate variability than altering the structure and function of a protein through random mutations, Wray said.

Called "promoters," these regulatory segments determine how much and how fast a protein is expressed rather than changing its structure or function.

The finding supports a growing consensus among evolutionary anthropologists that hominid divergence from the other great apes was fueled not by the origin of new genes, but by the speeding up or slowing down of the expression of existing genes.

In the studies, the researchers analyzed the sequence structure of the PDYN promoter segment in humans and in seven species of nonhuman primates: chimpanzees, bonobos, gorillas, orangutans, baboons, pig-tailed macaques and rhesus monkeys.

The researchers didn’t find significant mutational changes in the parts of the PDYN gene that controlled protein structure or function. Instead, most of the changes were in segments of the gene that controlled the regulation of PDYN. For example, the PDYN protein is identical in chimps and humans, but the human version is 20 percent more active.

The researchers also found a surprisingly large amount of genetic variation in the PDYN promoter segment among humans. The analyses showed higher differences between the different populations—which included Chinese, Papua New Guineans, (Asian) Indians, Ethiopians, Cameroonians, Austrians and Italians — than within them. Such a pattern is a signature of evolutionary selection, Wray said.

Still mysterious, however, is how the prodynorphin gene changes affect human neural development.

"We do know that not making enough prodynorphin causes clinical problems, but we don't know what having more of it did for us humans," Wray said. "We're hoping the clinical psychiatrists and psychologists can give us more insight into that aspect."